XIFAXAN (Page 5 of 6)

14.2 Hepatic Encephalopathy

The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada and Russia who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ≥2 episodes of HE associated with chronic liver disease in the previous 6 months.

A total of 299 subjects were randomized to receive either XIFAXAN (n=140) or placebo (n=159) in this study. Patients had a mean age of 56 years (range, 21-82 years), 81% <65 years of age, 61% were male and 86% White. At baseline, 67% of patients had a Conn score of 0 and 68% had an asterixis grade of 0. Patients had MELD scores of either <10 (27%) or 11 to 18 (64%) at baseline. No patients were enrolled with a MELD score of >25. Nine percent of the patients were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode. Other reasons for early study discontinuation included: adverse reactions (XIFAXAN 6%; placebo 4%), patient request to withdraw (XIFAXAN 4%; placebo 6%) and other (XIFAXAN 7%; placebo 5%).

The primary endpoint was the time to first breakthrough overt HE episode. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1.

Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month treatment period. Presented below in Figure 1 is the Kaplan-Meier event-free curve for all subjects (n=299) in the study.

Figure 1
(click image for full-size original)

Figure 1: Kaplan-Meier Event-Free Curves1 in HE Study (Time to First Breakthrough-HE Episode up to 6 Months of Treatment, Day 170) (ITT Population)

Figure 1: Kaplan-Meier Event-Free Curves1 in HE Study (Time to First Breakthrough-HE Episode up to 6 Months of Treatment, Day 170) (ITT Population)

Note: Open diamonds and open triangles represent censored subjects.

1 Event-free refers to non-occurrence of breakthrough HE.

When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, duration of current remission and diabetes. The differences in treatment effect could not be assessed in the following subpopulations due to small sample size: non-White (n=42), baseline MELD >19 (n=26), Child-Pugh Class C (n=31), and those without concomitant lactulose use (n=26).

HE-related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%) in the XIFAXAN and placebo groups respectively. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE-related hospitalizations by 50% during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2.

Figure 2
(click image for full-size original)

Figure 2: Kaplan-Meier Event-Free Curves1 in Pivotal HE Study (Time to First HE-Related Hospitalization in HE Study up to 6 Months of Treatment, Day 170) (ITT Population)

Figure 2: Kaplan-Meier Event-Free Curves1 in Pivotal HE Study (Time to First HE-Related Hospitalization in HE Study up to 6 Months of Treatment, Day 170) (ITT Population)

Note: Open diamonds and open triangles represent censored subjects.

1 Event-free refers to non-occurrence of HE-related hospitalization.

14.3 Irritable Bowel Syndrome with Diarrhea

The efficacy of XIFAXAN for the treatment of IBS-D was established in 3 randomized, multi‑center, double-blind, placebo-controlled trials in adult patients.

Trials 1 and 2 – Design

The first two trials, Trials 1 and 2 were of identical design. In these trials, a total of 1258 patients meeting Rome II criteria for IBS* were randomized to receive XIFAXAN 550 mg three times a day (n=624) or placebo (n=634) for 14 days and then followed for a 10-week treatment-free period. The Rome II criteria further categorizes IBS patients into 3 subtypes: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or alternating IBS (bowel habits alternating between diarrhea and constipation). Patients with both IBS-D and alternating IBS were included in Trials 1 and 2. XIFAXAN is recommended for use in patients with IBS-D.

*Rome II Criteria: At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: 1. Relieved with defecation; and/or 2. Onset associated with a change in frequency of stool; and/or 3. Onset associated with a change in form (appearance) of stool.

Symptoms that Cumulatively Support the Diagnosis of Irritable Bowel Syndrome:

– Abnormal stool frequency (for research purposes “abnormal” may be defined as greater than 3 bowel movements per day and less than 3 bowel movements per week); Abnormal stool form (lumpy/hard or loose/watery stool); Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); Passage of mucus; Bloating or feeling of abdominal distension.

Trial 3 — Design

Trial 3 evaluated repeat treatment in adults with IBS-D meeting Rome III criteria** for up to 46 weeks. A total of 2579 were enrolled to receive open-label XIFAXAN for 14 days. Of 2438 evaluable patients, 1074 (44%) responded to initial treatment and were evaluated over 22 weeks for continued response or recurrence of IBS-symptoms. A total of 636 patients had symptom recurrence and were randomized into the double-blind phase of the study. These patients were scheduled to receive XIFAXAN 550 mg three times a day (n=328) or placebo (n=308) for two additional 14-day repeat treatment courses separated by 10 weeks. See Figure 3.

Figure 3
(click image for full-size original)

Figure 3 Trial 3 Study Design

Figure 3 Trial 3 Study Design

The IBS-D population from the three studies had mean age of 47 (range: 18 to 88) years of which approximately 11% of patients were ≥65 years old, 72% were female and 88% were White.

**Rome III Criteria: Recurrent abdominal pain or discomfort (uncomfortable sensation not described as pain) at least 3 days/month in last 3 months associated with two or more of the following: 1. Improvement with defecation; 2. Onset associated with a change in frequency of stool; 3. Onset associated with a change in form (appearance) of stool.

Trials 1 and 2 — Results

Trials 1 and 2 included 1258 IBS-D patients (309 XIFAXAN, 314 placebo); (315 XIFAXAN, 320 placebo). The primary endpoint for both trials was the proportion of patients who achieved adequate relief of IBS signs and symptoms for at least 2 of 4 weeks during the month following 14 days of treatment. Adequate relief was defined as a response of “yes” to the following weekly Subject Global Assessment (SGA) question: “In regards to your IBS symptoms, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? [Yes/No].”

Adequate relief of IBS symptoms was experienced by more patients receiving XIFAXAN than those receiving placebo during the month following 2 weeks of treatment (SGA-IBS Weekly Results: 41% vs. 31%, p=0.0125; 41% vs. 32%, p=0.0263 (See Table 6).

Table 6. Adequate Relief of IBS Symptoms During the Month Following Two Weeks of Treatment
*
Confidence Interval
The p-value for the primary endpoint for Trial 1 and for Trial 2 was <0.05.

Endpoint

Trial 1

Trial 2

XIFAXAN

n=309

n (%)

Placebo

n=314

n (%)

Treatment

Difference

(95% CI *)

XIFAXAN

n=315

n (%)

Placebo

n=320

n (%)

Treatment

Difference

(95% CI *)

Adequate Relief of IBS Symptoms

126 (41)

98 (31)

10%

(2.1%, 17.1%)

128 (41)

103 (32)

8%

(1.0%, 15.9%)

The trials examined a composite endpoint which defined responders by IBS-related abdominal pain and stool consistency measures. Patients were monthly responders if they met both of the following criteria:

experienced a ≥30% decrease from baseline in abdominal pain for ≥2 weeks during the month following 2 weeks of treatment
had a weekly mean stool consistency score <4 (loose stool) for ≥2 weeks during the month following 2 weeks of treatment

More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in Trials 1 and 2 (see Table 7).

Table 7. Efficacy Responder Rates in Trial 1 and 2 During the Month Following Two Weeks of Treatment
*
Confidence Interval
The p-value for the composite endpoint for Trial 1 and 2 was <0.05 and <0.01, respectively.

Endpoint

Trial 1

Trial 2

XIFAXAN

n=309

n (%)

Placebo

n=314

n (%)

Treatment Difference

(95% CI *)

XIFAXAN

n=315

n (%)

Placebo

n=320

n (%)

Treatment Difference (95% CI *)

Abdominal Pain and Stool Consistency Responders

144 (47)

121 (39)

8%

(0.3%, 15.9%)

147 (47)

116 (36)

11%

(2.7%, 18.0%)

Abdominal Pain Responders

159 (51)

132 (42)

9%

(1.8%, 17.5%)

165 (52)

138 (43)

9%

(1.5%, 17.0%)

Stool Consistency Responders

244 (79)

212 (68)

11%

(4.4%, 18.2%)

233 (74)

206 (64)

10%

(2.3%, 16.7%)

Trial 3 — Results

In TARGET 3, 2579 patients were scheduled to receive an initial 14-day course of open-label XIFAXAN followed by 4 weeks of treatment-free follow-up. At the end of the follow-up period, patients were assessed for response to treatment. Patients were considered a responder if they achieved both of the following:

≥30% improvement from baseline in the weekly average abdominal pain score based on the daily question: “In regards to your specific IBS symptoms of abdominal pain, on a scale of 0-10, what was your worst IBS-related abdominal pain over the last 24 hours? ‘Zero’ means you have no pain at all; ‘Ten’ means the worst possible pain you can imagine”.
at least a 50% reduction in the number of days in a week with a daily stool consistency of Bristol Stool Scale type 6 or 7 compared with baseline where 6=fluffy pieces with ragged edges, a mushy stool; 7=watery stool, no solid pieces; entirely liquid.

Responders were then followed for recurrence of their IBS-related symptoms of abdominal pain or mushy/watery stool consistency for up to 20 treatment-free weeks.

When patients experienced recurrence of their symptoms of abdominal pain or mushy/watery stool consistency for 3 weeks of a rolling 4-week period, they were randomized into the double-blind, placebo-controlled repeat treatment phase. Of 1074 patients who responded to open-label XIFAXAN, 382 experienced a period of symptom inactivity or decrease that did not require repeat treatment by the time they discontinued, including patients who completed the 22 weeks after initial treatment with XIFAXAN. See Figure 3.

Overall, 1257 of 2579 patients (49%) were nonresponders in the open-label phase and per the study protocol were withdrawn from the study. Other reasons for discontinuation include: patient request (5%), patient lost to follow-up (4%), adverse reaction (3%), and other (0.8%).

There were 1074 (44%) of 2438 evaluable patients who responded to initial treatment with improvement in abdominal pain and stool consistency. The response rate for each IBS symptom during the open-label phase of Trial 3 is similar to the rates seen in Trials 1 and 2 (see Table 7). A total of 636 patients subsequently had sign and symptom recurrence and were randomized to the repeat treatment phase. The median time to recurrence for patients who experienced initial response during the open-label phase with XIFAXAN was 10 weeks (range 6 to 24 weeks).

The XIFAXAN and placebo treatment groups had similar baseline IBS symptom scores at the time of recurrence and randomization to the double-blind phase, but symptom scores were less severe than at study entry into the open-label phase.

Patients were deemed to have recurrent signs and symptoms by the following criteria: a return of abdominal pain or lack of stool consistency for at least 3 weeks during a 4-week follow-up period. The primary endpoint in the double-blind, placebo-controlled portion of the trial was the proportion of patients who were responders to repeat treatment in both IBS-related abdominal pain and stool consistency as defined above during the 4 weeks following the first repeat treatment with XIFAXAN. The primary analysis was performed using the worst case analysis method where patients with <4 days of diary entries in a given week are considered as non-responders for that week.

More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in the primary analysis in Trial 3 (see Table 8).

Table 8. Efficacy Responder Rates in Trial 3 in a Given Week for at Least 2 Weeks During Weeks 3 to 6 of the Double-Blind, First Repeat Treatment Phase
*
Confidence Intervals were derived based on CMH test adjusting for center and patients’ time to recurrence during maintenance phase.
Primary endpoint
Subjects were IBS-related abdominal pain and stool consistency responders if they were both weekly IBS-related abdominal pain responders and weekly stool consistency responders in a given week for at least 2 weeks during Weeks 3 to 6 in the double-blind first repeat treatment phase. Weekly responder in IBS-related abdominal pain was defined as a 30% or greater improvement from baseline in the weekly average abdominal pain score. Weekly responder in stool consistency was defined as a 50% or greater reduction in the number of days in a week with stool consistency of type 6 or 7 compared with baseline. The p-value for this composite endpoint was <0.05.

Placebo

(n=308)

n (%)

XIFAXAN

(n=328)

n (%)

Treatment

Difference

(95% CI *)

Combined Responder : Abdominal Pain and Stool Consistency Responders

97 (31)

125 (38)

7%

(0.9%, 16.9%)

Abdominal Pain Responders (>30% reduction in abdominal pain)

130 (42)

166 (51)

9%

(1.6%, 17.0%)

Stool Consistency Responders (>50% reduction from baseline in days/week with loose or watery stools)

154 (50)

170 (52)

2%

(-4.7%, 11.0%)

Thirty six of 308 (11.7%) of placebo patients and 56 of 328 (17.1%) of XIFAXAN-treated patients responded to the first repeat treatment and did not have recurrence of signs and symptoms through the treatment-free follow-up period (10 weeks after first repeat treatment). The response rate difference was 5.4% with 95% confidence interval (1.2% to 11.6%).

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